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To study whether there is a correlation between the macular and optic nerve morphological condition and the retinal ganglion cells (RGCs) and visual pathways' function, and to investigate whether visual acuity (VA) changes might be related to the morpho-functional findings in chronic non-arteritic ischemic optic neuropathy (NAION).In this retrospective study, 22 patients (mean age 62.12 ± 6.87) with chronic unilateral NAION providing 22 affected and 22 fellow eyes without NAION (NAION-FE), and 20 (mean age 61.20 ± 7.32) healthy control subjects were studied by spectral domain optical coherence tomography (Sd-OCT) for investigating macular thickness (MT) and volume (MV) of the whole (WR), inner (IR) and outer retina (OR), and the peripapillary retinal nerve fiber layer thickness (RNFL-T) measured overall and for all quadrants. Also, simultaneous 60' and 15' pattern electroretinogram (PERG) and visual evoked potentials (VEP) and VA were assessed. Differences of MT and MV of WR, IR, OR, and RNFL-T overall and for all quadrants, PERG amplitude (A), VEP implicit time (IT), and A and VA values between NAION eyes and controls were assessed by one-way analysis of variance. Pearson's test was used for regression analysis. A p value 0.01 was considered as significant.In NAION eyes as compared to NAION-FE eyes and controls, significant (p 0.01) changes of MT, MV of WR and IR, RNFL-T, 60' and 15' PERG A, VEP IT and A, and VA were found. No significant (p 0.01) OR changes were observed between groups. In NAION eyes, significant (p 0.01) correlations between MV of WR and IR and 15' PERG A were found. Overall, RNFL-T values were significantly correlated (p 0.01) with those of 60' PERG A and VEP IT and A; temporal RNFL-T values were correlated (p 0.01) with 15' PERG A and VEP IT and A ones. Temporal RNFL-T, MV-IR, and 15' PERG A as well as VEP IT were significantly (p 0.01) correlated with VA. Significant (p 0.01) linear correlations between 60' and 15' PERG A findings and the corresponding values of 60' and 15' VEP A were also found.Our findings suggest that in chronic NAION, there is a morpho-functional impairment of the IR, with OR structural sparing. VA changes are related to the impaired morphology and function of IR, to the temporal RNFL-T reduction and to the dysfunction of both large and small axons forming the visual pathway.

To study the outer retina morpho-functional characteristics and the choriocapillaris (CC) features in type 1 diabetic (T1D) patients, with and without signs of diabetic retinopathy (NPDR and NoDR). Twenty-five NPDR and 18 NoDR eyes were imaged by Optical Coherence Tomography Angiography. Ellipsoid zone (EZ) “normalized” reflectivity and CC perfusion density parameters, as flow deficits number (FDn), flow deficit average area (FDa) and flow deficit percentage (FD%), were analysed. Multifocal electroretinogram (mfERG) response amplitude densities (RADs) were measured. Mean EZ “normalized” reflectivity, CC FDn and FD% values, were similar (p > 0.05) in both groups, FDa was significant greater (p > 0.05) in NPDR compared with NoDR eyes. MfERG-RADs were similar in both groups. NPDR eyes showed a significant (p

Introduction Our aim was to evaluate the effects of 36 months of treatment with citicoline and vitamin B12 eye drops on macular function in patients with type 1 diabetes (DM1) with mild signs of non-proliferative diabetic retinopathy (NPDR). Methods A prospective, randomized, interventional, monocentric, double-masked study was conducted. Twenty patients with DM1 were enrolled and randomly divided into two groups: the DC group (10 patients; mean age ± standard deviation 46.86 ± 8.78 years) in which one eye of each patient was treated with citicoline and vitamin B12 eye drops (OMK2®, Omikron Italia srl, Italy, one drop thrice daily) for a period of 36 months; the DP group (10 patients; mean age ± standard deviation 47.89 ± 7.74 years) in which one eye of each patient was treated with placebo (eye drops containing hypromellose 0.3%, one drop thrice daily) for a period of 36 months. A total of 18 eyes (10 from the DP and 8 from the DC group, respectively) completed the study. In both groups, multifocal electroretinogram (mfERG) recordings were assessed at baseline and after 36 months. In mfERG analysis, the N1–P1 response amplitude density (RAD) evaluated in the 0–2.5° (ring 1), in the 2.5–5° (ring 2), in the 5–10° (ring 3), and in the 0–10° (ring 1 + ring 2 + ring 3) were considered. Results With respect to baseline, after 36 months of follow-up, the mfERG RADs recorded in R1, R2, R3, and R1 + R2 + R3 were significantly increased (i.e., R1 + R2 + R3 RAD from 21.552 ± 2.522 nV/degree2 at baseline to 26.912 ± 2.850 nV/degree2 at 36 months) in DC eyes, whereas in DP eyes they were significantly reduced (i.e., R1 + R2 + R3 RAD from 21.033 ± 3.574 nV/degree2 at baseline to 16.151 ± 3.571 nV/degree2 at 36 months). Conclusions This study indicates that patients with NPDR treated with citicoline and vitamin B12 eye drops for a 36-month period achieved an improvement of the macular bioelectrical responses detectable by mfERG recordings. By contrast, during the same period of follow-up, patients with NPDR treated with placebo showed a worsening of the macular function.

Background Bardet–Biedl syndrome (BBS) is a rare inherited multisystemic disorder with autosomal recessive or complex digenic triallelic inheritance. There is currently no treatment for BBS, but some morbidities can be managed. Accurate molecular diagnosis is often crucial for the definition of appropriate patient management and for the development of a potential personalized therapy. Methods We developed a next-generation-sequencing (NGS) protocol for the screening of the 18 most frequently mutated genes to define the genotype and clarify the mutation spectrum of a cohort of 20 BBS Italian patients. Results We defined the causative variants in 60% of patients; four of those are novel. 33% of patients also harboured variants in additional gene/s, suggesting possible oligogenic inheritance. To explore the function of different genes, we looked for correlations between genotype and phenotype in our cohort. Hypogonadism was more frequently detected in patients with variants in BBSome proteins, while renal abnormalities in patients with variations in BBSome chaperonin genes. Conclusions NGS is a powerful tool that can help understanding BBS patients’ phenotype through the identification of mutations that could explain differences in phenotype severity and could provide insights for the development of targeted therapy. Furthermore, our results support the existence of additional BBS loci yet to be identified. Electronic supplementary material The online version of this article (10.1186/s13052-019-0659-1) contains supplementary material, which is available to authorized users.

Background To evaluate the effects of Macuprev® supplementation on macular function and structure in intermediate age-related macular degeneration (AMD) along 6 months of follow-up. Methods In this double-blind, monocentric, randomized, and prospective study, 30 patients with intermediate AMD were enrolled and randomly divided into two age-similar groups: 15 patients (AMD-M group; mean age 68.50 ± 8.79 years) received 6-month oral daily supplementation with Macuprev® (Farmaplus Italia s.r.l., Italy, two tablets/day on an empty stomach, before meals; contained in total lutein 20 mg, zeaxanthin 4 mg, N-acetylcysteine 140 mg, bromelain 2500GDU 80 mg, vitamin D3 800 IU, vitamin B12 18 mg, alpha-lipoic acid 140 mg, rutin 157 mg, vitamin C 160 mg, zinc oxide 16 mg, Vaccinium myrtillus 36% anthocyanosides 90 mg, Ganoderma lucidum 600 mg) and 15 patients (AMD-P group; mean age 70.14 ± 9.87) received two tablets of placebo daily on an empty stomach, before meals. A total of 28 eyes, 14 from each AMD group, completed the study. Multifocal electroretinogram (mfERG) and spectral domain-optical coherence tomography (SD-OCT) were assessed at baseline and after 6 months. Results At 6-month follow-up, AMD-M eyes showed a significant increase of mfERG response amplitude density (RAD) recorded from the central macular areas (ring 1, 0–2.5°; ring 2, 2.5–5°), whereas non-significant changes of retinal and choroidal SD-OCT parameters were found when values were compared to baseline. Non-significant correlations between functional and structural changes were found. In AMD-P eyes, non-significant differences for each mfERG and SD-OCT parameters were observed at 6 months. Conclusions In intermediate AMD, Macuprev® supplementation increases the function of the macular pre-ganglionic elements, with no associated retinal and choroidal ultra-structural changes. Trial Registration ClinicalTrials.gov identifier, NCT03919019. Funding Research for this study was financially supported by the Italian Ministry of Health and Fondazione Roma. Article processing charges were funded by Farmaplus Italia s.r.l., Italy.

To evaluate the retinal function and the relative neural conduction along the visual pathway after treatment with citicoline in liposomal formulation (CLF) eye drops in patients with open angle glaucoma (OAG). Twelve OAG patients (mean age ± standard deviation 52.58 ± 11.39 years, intraocular pressure

Introduction This study aimed to evaluate whether treatment with fingolimod (FTY) may induce functional changes on the macular pre-ganglionic retinal elements in patients affected by relapsing–remitting multiple sclerosis (RR-MS) without optic neuritis (ON). Methods This case–control observational and retrospective study assessed multifocal electroretinogram (mfERG) responses from 35 healthy controls (mean age 43.58 ± 5.76 years), 41 patients with RR-MS without ON (mean age 40.64 ± 4.83 years, MS-noFTY group), and from 21 patients with RR-MS without ON (mean age 42.38 ± 12.34 years) and treated with fingolimod (Gilenya®, Novartis Europharm, 0.5 mg/day) (MS-FTY group). MfERG N1 and P1 implicit times (ITs), and N1–P1 response amplitude densities (RADs) were measured from concentric rings (R) with increasing foveal eccentricity: 0–5° (R1), 5–10° (R2), 10–15° (R3), 15–20° (R4), 20–25° (R5). We considered R1 and R2 as “central macular areas” and R3, R4 and R5 as “more eccentric retinal areas”. In the MS-FTY group, mfERG recordings were performed between 6 and 12 months (mean 7.2 ± 1.5 months) from the start of FTY. Results In the MS-FTY group, the mean values of mfERG N1 and P1 ITs and RADs detected in both central macular areas (R1 and R2) and in more eccentric retinal areas (R3, R4 and R5) were not significantly different (p > 0.01) with respect to those of control and MS-noFTY groups. Conclusions Our mfERG results suggest that the chronic use of FTY does not induce a dysfunction of pre-ganglionic retinal elements located in the 0–25° of central retina. Since FTY does not cause any retinal functional abnormality, we suggest that FTY treatment could not produce any toxic effect on pre-ganglionic retinal elements even in the absence of macular oedema.

Usher syndrome type 2A (USH2A) is a genetic disease characterized by bilateral neuro-sensory hypoacusia and retinitis pigmentosa (RP). While several methods, including electroretinogram (ERG), describe retinal function in USH2A patients, structural alterations can be assessed by optical coherence tomography (OCT). According to a recent collaborative study, RP can be staged considering visual acuity, visual field area and ellipsoid zone (EZ) width. The aim of this study was to retrospectively determine RP stage in a cohort of patients with USH2A gene variants and to correlate the results with age, as well as additional functional and morphological parameters. In 26 patients with established USH2A genotype, RP was staged according to recent international standards. The cumulative staging score was correlated with patients’ age, amplitude of full-field and focal flicker ERGs, and the OCT-measured area of sub-Retinal Pigment Epithelium (RPE) illumination (SRI). RP cumulative score (CS) was positively correlated (r = 0.6) with age. CS was also negatively correlated (rho = −0.7) with log10 ERG amplitudes and positively correlated (r = 0.5) with SRI. In USH2A patients, RP severity score is correlated with age and additional morpho-functional parameters not included in the international staging system and can reliably predict their abnormality at different stages of disease.

Cytidine 5’-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials).

Purpose Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. Methods First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. Results 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. Conclusion CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

The involvement of macular preganglionic elements&rsquo, function, during the neurodegenerative process of multiple sclerosis (MS), is controversial. In this case-control observational and retrospective study, we assessed multifocal electroretinogram (mfERG) responses from 41 healthy Controls, 41 relapsing-remitting MS patients without optic neuritis (ON) (MS-noON Group) and 47 MS patients with ON: 27 with full recovery of high-contrast best corrected visual acuity (BCVA) (MS-ON-G Group) and 20 with poor recovery (between 0.2 and 1 LogMAR) of BCVA, (MS-ON-P Group). In the latter Group, Sd-OCT macular volumes and thicknesses of whole and inner and outer retina were measured. MfERG N1 and P1 implicit times (ITs), and N1-P1 response amplitude densities (RADs), were measured from concentric rings (R) with increasing foveal eccentricity: 0&ndash, 5&deg, (R1), 5&ndash, 10&deg, (R2), 10&ndash, 15&deg, (R3), 15&ndash, 20&deg, (R4), 20&ndash, 25&deg, (R5), and from retinal sectors (superior, nasal, inferior and temporal) between 0&ndash, and 0&ndash, In the MS-ON-P Group, mean mfERG RADs detected from R1 (0&ndash, ) and from the central nasal sector (0&ndash, ) were significantly reduced (p &lt, 0.01) with respect to those of the Control, MS-noON and MS-ON-G Groups. No other significant differences between Groups for any mfERG parameters were found. All Sd-OCT measurements, apart from the inner retina macular volume in the central 1 mm, were significantly reduced in MS-ON-P patients compared to Controls. The functional impairment in the MS-ON-P Group was associated but not correlated with structural changes of the outer and inner retinal layers in corresponding retinal Areas and Sectors. Our results suggest that in MS, exclusively after ON with poor recovery of BCVA, the neurodegenerative process can induce dysfunctional mechanisms involving photoreceptors and bipolar cells of the fovea and of the more central nasal macular area.

The involvement of macular function in its preganglionic elements, during the neurodegenerative process of multiple sclerosis (MS), is controversial. In this case-control observational and retrospective study, we assessed multifocal electroretinogram (mfERG) responses from 41 healthy Controls, 41 relapsing-remitting MS patients without optic neuritis (ON) (MS-noON Group), 47 MS patients with ON: 27 with full recovery of high-contrast best corrected visual acuity (BCVA) (MS-ON-G Group) and 20 with poor recovery of BCVA (MS-ON-P Group). MfERG N1 and P1 implicit times (ITs), and N1-P1 response amplitude densities (RADs) were measured from concentric rings (R) with increasing foveal eccentricity: 0-5° (R1), 5-10° (R2), 10-15° (R3), 15-20° (R4), 20- 25° (R5), and from retinal sectors [superior, nasal, inferior and temporal] between 0-15° and 0- 25°. In MS-ON-P Group, mean mfERG RADs detected from R1 (0-5°) and from the central nasal quadrant (0-15°) were significantly reduced (p

Purpose: To investigate on the morphology of the macular inner (IR) and outer (OR) layers in multiple sclerosis (MS) patients with and without history of optic neuritis (ON), followed by good or poor recovery of best corrected visual acuity (BCVA).Methods: Thirty-five normal control subjects and 93 relapsing remitting MS patients were enrolled. Of this, 40 MS patients without ON (MS-noON, 40 eyes), 27 with history of ON and good BCVA recovery (MS-ON-G, 27 eyes), and 26 with history of ON and poor BCVA recovery (MS-ON-P, 26 eyes) were studied. Controls and MS patients underwent an extensive ophthalmological examination including spectral-domain optical coherence tomography evaluating in 3 localized macular areas (0–1 mm, Area 1; 1–3 mm, Area 2; 3- 6 mm, Area 3), volumes (MV), and thicknesses (MT) of the whole retina (WR), further segmented in IR and OR. The differences of MV and MT between the groups were tested by ANOVA. In the MS-ON-P group, the correlations between MV and MT and BCVA were evaluated by Pearson's test.Results: When compared to controls, the MS-noON group showed not significantly (p > 0.01) different MVs, whereas MTs were significantly (p < 0.01) reduced in the evaluation of WR and IR. In the MS-ON-G group, a significant (p < 0.01) reduction of WR and IR MVs and MTs was found in Areas 2 and 3; OR MVs and MTs were similar (p > 0.01) to controls. In the MS-ON-P group a significant (p < 0.01) reduction of WR, IR, and OR MVs and MTs was detected in all areas; the BCVA reduction was significantly (p < 0.01) correlated with WR and IR MVs and MTs.Conclusions: In MS without history of ON or when ON is followed by a good BCVA recovery, the neurodegenerative process is limited to IR macular layers; in the presence of ON, with a poor BCVA recovery, a morphological impairment of both IR and OR macular layers occurs.

Obesity phenotype can be manifested as an isolated trait or accompanied by multisystem disorders as part of a syndromic picture. In both situations, same molecular pathways may be involved to different degrees. This evidence is stronger in syndromic obesity, in which phenotypes of different syndromes may overlap. In these cases, genetic testing can unequivocally provide a final diagnosis. Here we describe a patient who met the diagnostic criteria for Alström syndrome only during adolescence. Genetic testing was requested at 25 years of age for a final confirmation of the diagnosis. The genetic diagnosis of Alström syndrome was obtained through a Next Generation Sequencing genetic test approach using a custom-designed gene panel of 47 genes associated with syndromic and non-syndromic obesity. Genetic analysis revealed a novel homozygous frameshift variant p.(Arg1550Lysfs*10) on exon 8 of the ALMS1 gene. This case shows the need for a revision of the diagnostic criteria guidelines, as a consequence of the recent advent of massive parallel sequencing technology. Indications for genetic testing reported in these currently accepted diagnostic criteria for Alström syndrome, were drafted when sequencing was expensive and time consuming. Nowadays, Next Generation Sequencing testing could be considered as first line diagnostic tool not only for Alström syndrome but, more generally, for all those atypical or not clearly distinguishable cases of syndromic obesity, thus avoiding delayed diagnosis and treatments. Early diagnosis permits a better follow-up and pre-symptomatic interventions.

Spinocerebellar ataxia type 1 (SCA-ATXN1) is an autosomal dominant, neurodegenerative disease, caused by CAG repeat expansion in the ataxin-1 gene (ATXN1). In isolated reports of patients with neurological signs [symptomatic patients (SP)], macular abnormalities have been described. However, no reports exist about macular anomalies in SCA1 subjects carrying the ATXN1 mutation without neurological signs [not symptomatic carriers (NSC)]. Therefore, the main aim of our work was to evaluate whether the macular functional and morphological abnormalities could be detectable in SP, genetically confirmed and with neurological signs, as well as in SCA-ATXN1-NSC, harboring pathogenic CAG expansion in ATXN1. In addition, we investigated whether the macular involvement could be associated or not to an impairment of RGCs and of their fibers and of the neural conduction along the visual pathways. Herein, nine SCA-ATXN1 subjects (6 SP and 3 NSC) underwent the following examinations: visual acuity and chromatic test assessments, fundus oculi (FO) examination, macular and peripapillary retinal nerve fiber layer thickness (RNFL-T) analysis by Spectral domain-Optical Coherence Tomography (Sd-OCT) acquisition, multifocal electroretinogram (mfERG), pattern reversal electroretinogram (PERG) and visual evoked potentials (VEP) recordings. In four eyes of two SP, visual acuity reduction and chromatic abnormalities were observed, in three of them FO changes associated with macular thinning and outer retinal defects were also detected. In three NSC eyes, slight FO abnormalities were associated with qualitative macular morphological changes. By contrast, abnormal mfERG responses (exclusively from foveal and parafoveal areas) were detected in all SP and NSC (18 eyes). No abnormalities of PERG values, RNFL-T, and VEP responses were found, but in one SP, presenting abnormal papillo-macular bundle neural conduction. Results from our SCA-ATXN1 cohort suggest that a macular dysfunction, detectable by mfERG recordings, may occur in the overt disorder, and unexpectedly in the stage of the disease in which there is still an absence of neurological signs. In NSC, an exclusive dysfunction of preganglionic macular elements can be observed, and this is associated with both normal RGCs function and neural conduction along the visual pathways.

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for Mendelian glaucomas, a large heterogeneous group of inherited disorders, classified according to age of onset as congenital glaucoma, juvenile glaucoma and age-related glaucoma. Variations in the TEK, MYOC, ASB10, NTF4, OPA1, WDR36 and OPTN genes are inherited in an autosomal dominant manner and variations in the CYP1B1 and LTBP2 genes have autosomal recessive inheritance. The prevalence of congenital glaucoma is estimated at 1-9 per 100 000, that of juvenile glaucoma at 1 per 50 000, while there is insufficient data to establish the prevalence of age-related glaucoma. Clinical diagnosis is based on clinical findings, age of onset, family history, ophthalmological examination, intraocular pressure, gonioscopy and fundoscopy. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

PurposeTo evaluate whether treatment with Citicoline in oral solution (OS-Citicoline) would increase visual function, retinal ganglion cells (RGCs) function, and neural conduction along visual pathways (neuroenhancement), and/or induce preservation of RGCs fibers' loss (neuroprotection) in non-arteritic ischemic optic neuropathy (NAION), a human model of neurodegeneration.MethodsThirty-six patients with NAION and 20 age-matched controls were enrolled. Nineteen NAION patients received 500 mg/day of OS-Citicoline for a 6-month period followed by 3-month of wash-out (NC Group); 17 NAION patients were not treated (NN Group) from baseline to 9 months. In all subjects at baseline, and in NC and NN eyes at 6 and 9 months of follow-up, we assessed Visual Acuity (VA), Pattern Electroretinogram (PERG), Visual Evoked Potentials (VEP), retinal nerve fiber layer thickness (RNFL-T), and Humphrey 24-2 visual field mean deviation (HFA MD). Mean differences were statistically evaluated with ANOVA between Groups, and linear correlations were analysed with Pearson's test.ResultsAt 6 months, significant differences between groups for all parameters were observed (ANOVA, pConclusionsOS-Citicoline treatment induced neuroenhancement (improvement in RGCs function and neural conduction along visual pathways related to improvement of visual field defects) and neuroprotection (unmodified or improved RNFL morphological condition) in a human model of NAION involving fast RGCs degeneration.Trial registrationClinicalTrials.gov NCT03758118.

Background Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the BEST1 gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium. Methods Here we describe the spectrum of BEST1 variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands. Results Thirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All BEST1 variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual BEST1 variants. Conclusions Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.

We studied the scientific literature and disease guidelines in order to summarize the clinical utility of genetic testing for Norrie disease. The disease is caused by variations in the NDP gene. Its prevalence is currently unknown. Inheritance is X-linked recessive. Clinical diagnosis is based on clinical findings, color vision testing, optical coherence tomography, ophthalmological examination and electroretinography. The genetic test is useful for confirming diagnosis, and for differential diagnosis, couple risk assessment and access to clinical trials.

Purpose: To assess changes of retinal ganglion cells (RGCs) and visual pathways’ function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase. Design: Retrospective case series. Participants: Twenty-two patients with LHON (mean age, 36.3±9.3 years) in the “chronic phase” of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five age-similar healthy participants, providing 25 eyes, served as controls. Methods: Pattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60ʹ and 15ʹ checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of test–retest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA. Main Outcome Measures: Changes of individual and mean absolute values of 60ʹ and 15ʹ PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group. Results: At baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P < 0.01) different with respect to control values. In the LHON group, at 6 and 12 months of follow-up, the majority of eyes showed unmodified (within 95% CL) PERG and VEP values, and mean absolute values of these measures were not significantly (P > 0.01) different from baseline values. Conclusions: In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON.

Objectives. It has been already confirmed that retinal neurodegeneration has a predictive value in the development of microvascular alterations in diabetic retinopathy. However, no data are available on the association between neuroretinal dysfunction and peripheral motor unit loss. Our study, therefore, was aimed at investigating the hypothesis that retinal neurodegeneration could be considered an early marker of diabetic peripheral neuropathy (DPN). Methods. 20 T1DM patients with no symptoms/signs of peripheral polyneuropathy, without DR or with very mild nonproliferative DR, and 14 healthy controls (C) age- and gender-matched were enrolled. The following electrophysiological tests were performed: standard nerve conduction studies (NCS) and incremental motor unit number estimation (MUNE) from the abductor hallux (AH) and abductor digiti minimi (ADM). Neuroretinal function was studied by multifocal electroretinogram (MfERG) recordings, measuring response amplitude density (RAD) and implicit time (IT) from rings and sectors of superior (S)/inferior (I)/temporal (T)/nasal (N) macular sectors up to 10 degrees of foveal eccentricity. Results. MfERG RADs from rings and sectors were significantly reduced in T1DM (p<0.05) vs. C. ADM MUNE and AH MUNE were significantly decreased in T1DM (p=0.039 and p<0.0001, respectively) vs. C. A positive correlation between mean MfERG RADs from the central 5 degrees of the four (S, I, T, and N) macular sectors and lower limb motor unit number (r=0.50, p=0.041; r=0.64, p=0.005; r=0.64, p=0.006; and r=0.61, p=0.010, respectively) was observed in T1DM patients. No abnormalities of NCS were found in any subject. Conclusions. The motor unit loss on the one hand and neuroretinal dysfunction on the other hand are already present in T1DM patients without DPN. The relationship between neuroretinal dysfunction and motor unit decline supports the hypothesis that neuroretina may represent a potential “window” to track the early neurogenic damage in diabetes.

Purpose The purpose of this study was to evaluate macular preganglionic function and to verify its relationship with retinal and choroidal morphology in patients with intermediate age-related macular degeneration (iAMD) patients. Methods All included patients performed multifocal electroretinogram (mfERG) for investigating on macular function from the central 15° of foveal eccentricity, spectral domain optical coherence tomography (SD-OCT) for studying retinal structure, enhanced depth imaging OCT (EDI-OCT) for the measure of choroidal vascularity index (CVI), and OCT-angiography (OCTA) for the evaluation of vessel density (VD) in the superficial and deep capillary plexus, and choriocapillaris (CC) layer. Results Twenty-seven patients with iAMD and 20 age-matched control eyes were analyzed. Significantly (P < 0.01) delayed and reduced mfERG responses in the central 0 to 2.5°, paracentral 2.5 to 5°, and overall 0 to 5° areas, as well as increased CVI values in both foveal (1 mm centered to the fovea) and fovea + parafovea areas (3 mm centered to the fovea), increased foveal and parafoveal (annular area of 1–3 mm centered to the fovea) retinal pigment epithelium thickness, and volume and parafoveal outer retinal volume were found in iAMD eyes as compared to controls. Moreover, iAMD eyes showed significantly (P < 0.01) reduced foveal and parafoveal OCTA-VD values in the CC layer when compared to controls. In the iAMD group, not significant (P > 0.01) correlations were found between morphological and functional parameters. Conclusions Our findings support a dysfunction of photoreceptors and bipolar cells in both foveal and parafoveal areas in the presence of outer retina, CC, and choroidal structural changes, however, not significantly correlated. The observed enlargement of luminal choroidal area (measured by CVI) is possibly compensatory to CC vascular insufficiency.

To investigate the function of localized retinal areas in highly selected type 1 diabetes mellitus patients (DM1) with no or mild signs of diabetic retinopathy (NO DR and NPDR, respectively) and its correlation with age, diabetes duration and glycemic control. Multifocal electroretinograms (mfERG) were recorded in 35 eyes of 18 NO DR patients and 38 eyes of 19 NPDR patients. Thirty-one eyes of 17 normal subjects were enrolled as controls. N1-P1 response amplitude densities (RADs) and P1 implicit times (ITs) from isolated (R1: 0°–2.5°, R2: 2.5°–5°, R3: 5°–10°) and combined (R1 + R2, R2 + R3 and R1 + R2 + R3) annular rings and from four retinal sectors (nasal, N; temporal, T; superior, S and inferior, I) with increasing eccentricities up to 10° (S1, S2, S3, S1 + S2, S1 + S2 + S3) were measured. The statistical differences between DM1 groups and controls were tested by ANOVA. The electrophysiological data were correlated with age, duration of diabetes and glycated hemoglobin (HbA1c) level using the Pearson’s test. MfERG RADs, but not ITs, from all isolated and combined rings and sectors up to 10° of foveal eccentricity were statistically different between DM1 groups compared to controls. No significant differences were found between NO DR and NPDR patients. The mfERG abnormalities of the central retinal areas were correlated significantly with age in both DM1 groups and with diabetes duration mainly in NPDR group. In DM1 patients, localized retinal dysfunction, described by reduced mfERG RAD, can be observed also in the absence of clinical signs of DR and it is related to aging.

Purpose Recent studies show that patients with Usher syndrome type 2 (USH2) have abnormal cone structure and density in the central retina. This occurs in the presence of normal acuity, opening the quest for additional sensitive functional measures of central cone function in USH. We tested here whether focal macular cone electroretinogram (fERG) could be such a tool. Methods This retrospective study of central cone function loss was based on data from 47 patients with USH2 from the Ophthalmology Department of the Policlinico Gemelli/Catholic University in Rome. The analysis focused on the decrease of the fERG, obtained in response to a 41-Hz sinusoidal modulation of a uniform field presented to the central 18°, generated by red light-emitting diodes (LEDs) and superimposed on an equiluminant steady adapting background. fERG decrease was compared with the decrease of best-corrected visual acuity and Goldmann kinetic perimetry V4E field. Results fERG follow-up data document a severe and precocious loss of central cone function in USH2 patients, preceding losses in other measures of cone function. fERG is already reduced to 40% of control at the beginning of the second decade of life, and by 25 years of age, all USH2 patients have fERGs less than 30% of control values. Conclusions fERG represents a sensitive tool to evaluate central cone function in USH2, anticipating the decline of other central cone function measures, such as visual acuity and Goldmann perimetry.

Background Retinal ganglion cells (RGCs) are the nervous retinal elements which connect the visual receptors to the brain forming the nervous visual system. Functional and/or morphological involvement of RGCs occurs in several ocular and neurological disorders and therefore these cells are targeted in neuroprotective strategies. Cytidine 5-diphosphocholine or Citicoline is an endogenous compound that acts in the biosynthesis of phospholipids of cell membranes and increases neurotransmitters' levels in the Central Nervous System. Experimental studies suggested the neuromodulator effect and the protective role of Citicoline on RGCs. This review aims to present evidence of the effects of Citicoline in experimental models of RGCs degeneration and in human neurodegenerative disorders involving RGCs. Methods All published papers containing experimental or clinical studies about the effects of Citicoline on RGCs morphology and function were reviewed. Results In rodent retinal cultures and animal models, Citicoline induces antiapoptotic effects, increases the dopamine retinal level, and counteracts retinal nerve fibers layer thinning. Human studies in neurodegenerative visual pathologies such as glaucoma or non-arteritic ischemic neuropathy showed a reduction of the RGCs impairment after Citicoline administration. By reducing the RGCs' dysfunction, a better neural conduction along the post-retinal visual pathways with an improvement of the visual field defects was observed. Conclusion Citicoline, with a solid history of experimental and clinical studies, could be considered a very promising molecule for neuroprotective strategies in those pathologies (i.e. Glaucoma) in which morpho-functional changes of RGCc occurs.

Purpose: To assess preganglionic retinal function using multifocal electroretinogram (mfERG) in patients affected by dominant optic atrophy (DOA) stratified by OPA1 gene mutation. Methods: Multifocal electroretinogram (mfERG) was recorded in 18 DOA patients (DOA group, 35 eyes) and 25 age-matched healthy subjects (control group, 25 eyes). Patients were stratified in two groups based on gene mutation: missense mutation (DOA-M group, 11 eyes) and mutation causing haploinsufficiency (DOA-H group, 24 eyes). The mfERG N1-P1 response amplitude density (RAD) has been evaluated in five annular retinal areas with different eccentricity from the fovea (ring 1: 0–5 degrees, R1; ring 2: 5–10 degrees, R2; ring 3: 10–15 degrees, R3; ring 4: 15–20 degrees, R4; and ring 5: 20–25 degrees, R5) and in eight sectors on the basis of the retinal topography: temporal–superior (TS), temporal–inferior (TI), nasal–superior (NS) and nasal–inferior (NI), temporal (T), superior (S), nasal (N) and inferior (I). Results: Compared to controls, DOA group revealed a significant reduction in N1-P1 RADs values in R1-R4 rings and in TI, NS and N sectors [analysis of variance (ANOVA), pÂ

This study evaluated the safety and tolerability of ocular RS1 adeno-associated virus (AAV8-RS1) gene augmentation therapy to the retina of participants with X-linked retinoschisis (XLRS). XLRS is a monogenic trait affecting only males, caused by mutations in the RS1 gene. Retinoschisin protein is secreted principally in the outer retina, and its absence results in retinal cavities, synaptic dysfunction, reduced visual acuity, and susceptibility to retinal detachment. This phase I/IIa single-center, prospective, open-label, three-dose-escalation clinical trial administered vector to nine participants with pathogenic RS1 mutations. The eye of each participant with worse acuity (≤63 letters; Snellen 20/63) received the AAV8-RS1 gene vector by intravitreal injection. Three participants were assigned to each of three dosage groups: 1e9 vector genomes (vg)/eye, 1e10 vg/eye, and 1e11 vg/eye. The investigational product was generally well tolerated in all but one individual. Ocular events included dose-related inflammation that resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in a dose-related fashion, but no antibodies against RS1 were observed. Retinal cavities closed transiently in one participant. Additional doses and immunosuppressive regimens are being explored to pursue evidence of safety and efficacy (ClinicalTrials.gov: NCT02317887).

Strategies aimed at invoking synaptic plasticity have therapeutic potential for several neurological conditions. The human retinal synaptic disease X-linked retinoschisis (XLRS) is characterized by impaired visual signal transmission through the retina and progressive visual acuity loss, and mice lacking retinoschisin (RS1) recapitulate human disease. Here, we demonstrate that restoration of RS1 via retina-specific delivery of adeno-associated virus type 8-RS1 (AAV8-RS1) vector rescues molecular pathology at the photoreceptor-depolarizing bipolar cell (photoreceptor-DBC) synapse and restores function in adult Rs1-KO animals. Initial development of the photoreceptor-DBC synapse was normal in the Rs1-KO retina; however, the metabotropic glutamate receptor 6/transient receptor potential melastatin subfamily M member 1-signaling (mGluR6/TRPM1-signaling) cascade was not properly maintained. Specifically, the TRPM1 channel and G proteins Gαo, Gβ5, and RGS11 were progressively lost from postsynaptic DBC dendritic tips, whereas the mGluR6 receptor and RGS7 maintained proper synaptic position. This postsynaptic disruption differed from other murine night-blindness models with an electronegative electroretinogram response, which is also characteristic of murine and human XLRS disease. Upon AAV8-RS1 gene transfer to the retina of adult XLRS mice, TRPM1 and the signaling molecules returned to their proper dendritic tip location, and the DBC resting membrane potential was restored. These findings provide insight into the molecular plasticity of a critical synapse in the visual system and demonstrate potential therapeutic avenues for some diseases involving synaptic pathology.

The aim of the present study was to evaluate the short-term effects of the vision trainer rehabilitation technique on retinal and post-retinal function in young amblyopic patients outside the critical visual developmental period. Twenty-one patients (mean age 12.2 ± 2.7 years, ranging from 9.1 to 18 years) affected by unilateral anisometropic amblyopia were studied, providing 21 amblyopic eyes (AE) and 21 sound eyes (SE). Thirty eyes from 15 age-similar normal subjects served as controls. All subjects underwent extensive ophthalmologic characterization to exclude any disease not related to amblyopia. All AE were subjected to rehabilitation sessions performed by the Retimax vision trainer (VT) program. The protocol consisted of 2 sessions per week, each lasting 10 min, for 10 consecutive weeks. Before and after the rehabilitation, electrophysiological [pattern electroretinogram (PERG) and visual evoked potential (VEP)] and psychophysical [best corrected visual acuity (BCVA) and microperimetry] data were collected from AE and SE. When comparing baseline data with those collected at the end of the study, PERG P50-N95 amplitude and BCVA values from AE had improved significantly by the end of the study (p

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7–19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR: FZD4, LRP5, TSPAN12, and NDP. Clinical and genetic evaluations were extended to relatives of probands positive to genetic testing. Six out of eight probands (75%) showed a genetic variation probably related to the phenotype. We identified four novel genetic variants, one variant already described in association with Norrie disease and one previously described linked to autosomal dominant FEVR. Pedigree analysis of patients led to the classification of four autosomal dominant cases of FEVR (caused by FZD4 and TSPAN12 variants) and two X-linked FEVR probands (NDP variants). None of the patients showed variants in the LRP5 gene. This study represents the largest cohort study in Italian FEVR patients. Our findings are in agreement with the previous literature confirming that FEVR is a clinically and genetically heterogeneous retinal disorder, even when it manifests in the same family.

Familial exudative vitreoretinopathy (FEVR) is a complex disorder characterized by incomplete development of the retinal vasculature. Here, we report the results obtained on the spectrum of genetic variations and correlated phenotypes found in a cohort of Italian FEVR patients. Eight probands (age range 7-19 years) were assessed by genetic analysis and comprehensive age-appropriate ophthalmic examination. Genetic testing investigated the genes most widely associated in literature with FEVR

To assess whether infantile visual deprivation induced by developmental cataract may influence the cone-driven retinal function in humans. A total of 14 patients with history of bilateral developmental cataract (DC), who had undergone uncomplicated cataract extraction surgery and intraocular lens implant, and 14 healthy subjects (HS) were enrolled. All patients underwent complete ophthalmological and orthoptic evaluations and best-corrected visual acuity measurement. Light-adapted full-field electroretinograms (ERG) and photopic negative responses (PhNR) were recorded to obtain a reliable measurement of the outer/inner retinal function and of the retinal ganglion cells’ function, respectively. Mean values of light-adapted ERG a- and b-wave implicit times were slightly delayed when compared to HS values. Light-adapted ERG a-wave amplitude mean values showed borderline values (p = 0.001), whereas a-wave amplitude analysis at 5 ms, b-wave and PhNR amplitude mean values showed no significant differences when compared to control values. No significant correlations were found when age at surgery, time elapsed from surgery, duration of the visual deprivation, age at examination, age at first detection of the opacity, BCVA and electrophysiological parameters were plotted together. Coherently with morphological studies, the extremely light bioelectrical impairment of the cone pathway in our cohort of patients describes minimal functional abnormalities of a well-structured retina that is not completely mature. Our present results, combined to those of our previous work on congenital cataracts, allow us to enhance the comprehension of functional developmental mechanisms of children’s retinas and highlight the relevance of the timely treatment of lens opacities during infancy.

BACKGROUND Osteoporosis-pseudoglioma syndrome is a very rare disease mainly characterized by severe eye abnormalities and osteoporosis but also causing a broader range of clinical features. The syndrome is associated with homozygous or compound heterozygous variations in the LRP5 gene. In this report, we describe two children with a severe early-onset form of familial exudative vitreoretinopathy associated with skeletal abnormalities. MATERIALS AND METHODS Two probands (4 and 7 years of age respectively) and their parents were assessed by genetic analysis and comprehensive ophthalmic examination. RESULTS In both probands, the diagnosis of osteoporosis-pseudoglioma syndrome was confirmed by detection of three new pathogenic LRP5 variants: p.(Asp379Asn), found in the homozygous state in one proband, and p.(Asp203Ala) in the compound heterozygous state with p.(Cys612Valfs*25) in the other. The clinical and genetic study was extended to their parents, confirming that heterozygous carriers may also have incomplete clinical manifestation of this syndrome. CONCLUSIONS To our knowledge, these are the first two cases of the syndrome described in Italy. Genetic testing proved to be fundamental for definition of the syndrome and confirms the importance of early detection of LRP5 variants for management of systemic features of the disease in patients and carrier relatives.

Oral form of citicoline, a nootropic and neuroprotective drug in use for almost five decades, recently was pronounced a food supplement in both USA and EU. The idea of adding citicoline to topical treatment of primary open angle glaucoma (POAG) aimed at decreasing intraocular pressure (IOP) appeared as a logical consequence of accepting neurodegenerative character of this disease. Experimental data, and also few clinical studies indicate that this substance has potential to counteract some important pathological mechanisms which seem to contribute to POAG initiation and progression, such as excitotoxicity and oxidative stress.

PURPOSE: To investigate bilateral symmetry of visual impairment in cone-rod dystrophy (CRD) patients and understand the feasibility of clinical trial designs treating one eye and using the untreated eye as an internal control. METHODS: This was a retrospective study of visual function loss measures in 436 CRD patients followed at the Ophthalmology Department of the Catholic University in Rome. Clinical measures considered were best-corrected visual acuity, focal macular cone electroretinogram (fERG), and Ganzfeld cone-mediated and rod-mediated electroretinograms. Interocular agreement in each of these clinical indexes was assessed by t- and Wilcoxon tests for paired samples, structural (Deming) regression analysis, and intraclass correlation. Baseline and follow-up measures were analyzed. A separate analysis was performed on the subset of 61 CRD patients carrying likely disease-causing mutations in the ABCA4 gene. RESULTS: Statistical tests show a very high degree of bilateral symmetry in the extent and progression of visual impairment in the fellow eyes of CRD patients. CONCLUSIONS: These data contribute to a better understanding of CRDs and support the feasibility of clinical trial designs involving unilateral eye treatment with the use of fellow eye as internal control.

SPG56 is an autosomal recessive form of hereditary spastic paraplegia (HSP) associated with mutations in CYP2U1. There is no clear documentation of visual impairment in the few reported cases of SPG56, although this form is complex on clinical ground and visual deficit are extremely frequent in complicated HSP. We report three patients in a consanguineous family harboring the novel homozygous c.1168C>T (p.R390*) in SPG56/CYP2U1, and showing a pigmentary degenerative maculopathy associated with progressive spastic paraplegia. Furthermore, we characterized precisely the ophthalmologic phenotype through indirect ophthalmoscopy, retinal optical coherence tomography and visual evoked potentials. This is the first formal report of pigmentary degenerative maculopathy associated with a CYP2U1 homozygous mutation.

X-linked retinoschisis (XLRS) is a retinal disease caused by mutations in the gene encoding the protein retinoschisin (RS1) and is one of the most common causes of macular degeneration in young men. Our therapeutic approach for XLRS is based on the administration of AAV8-scRS/IRBPhRS, an adeno-associated viral vector coding the human RS1 protein, via the intravitreal (IVT) route. Two Good Laboratory Practice studies, a 9-month study in New Zealand White rabbits (n = 124) injected with AAV8-scRS/IRBPhRS at doses of 2E9, 2E10, 2E11, and 1.5E12 vector genomes/eye (vg/eye), and a 6-month study in Rs1-KO mice (n = 162) dosed with 2E9 and 2E10 vg/eye of the same vector were conducted to assess ocular and systemic safety. A self-resolving, dose-dependent vitreal inflammation was the main ocular finding, and except for a single rabbit dosed with 1.5E12 vg/eye, which showed a retinal detachment, no other ocular adverse event was reported. Systemic toxicity was not identified in either species. Biodistribution analysis in Rs1-KO mice detected spread of vector genome in extraocular tissues, but no evidence of organ or tissues damage was found. These studies indicate that IVT administration of AAV8-scRS/IRBPhRS is safe and well tolerated and support its advancement into a phase 1/2a clinical trial for XLRS.

Right chorioretinitis and bilateral pseudopapilledema were firstly appreciated in a 9-month-old child with neonatal findings of aseptic chronic meningitis, framed in the context of CINCA syndrome at 1 year. Therapeutical response to various combinations of drugs was inconsistent until 7 years, when anakinra was started with immediate clinical and laboratory improvement. A state of severe retinal dystrophy of post-inflammatory origin became evident on funduscopy, optical coherence tomography and visual electrophysiology tests at the age of 10 years, which remained stationary after 1 year of anakinra treatment.

Purpose: To assess regional cone-mediated function in age-related maculopathy (ARM) by focal electroretinograms (FERGs), and to compare FERGs with morphologic changes and perimetric sensitivity at corresponding locations. Methods: Twenty-six ARM patients and 12 age-matched controls were evaluated. FERGs were elicited by either a central (0–2.25°, C) or a paracentral annular (2.25–9°, PC) flickering (41 Hz) field, presented on a light-adapting background. Morphological changes (soft drusen and/or retinal pigment epithelium defects) at matched locations were assessed by fundus photography and fluorescein angiography. Perimetric sensitivity was measured by Octopus 10° program (tM2). Results: When compared to controls, mean C and PC FERG amplitudes of patients were reduced (p < 0.01), and the mean PC FERG phase was delayed (p < 0.01). Both FERG delays and morphologic lesions tended to involve to a greater extent the PC compared to the C region. In the C region, perimetric losses were correlated with the extent of morphologic lesions (p < 0.05). In the PC region, perimetric losses were correlated with FERG amplitudes (p < 0.05). Conclusions: In ARM, FERG losses are eccentricity-dependent, not quantitatively linked to retinal morphology, and correlated with perimetric losses, suggesting a heterogeneous dysfunction with loss of both C and PC perimetric sensitivities.

Purpose:To determine the number of patients 4 years and younger who were hospitalized and operated on for congenital or infantile cataracts in Italy from 1999 through 2004.Methods:A retrospective review was performed of the Ministry of Health database on hospital admissions in Italy from 1999 through 2004.Results:In patients younger than 1 year, the mean number of admissions for congenital or infantile cataract was 3.78 and the mean number of admissions involving cataract surgery per 10,000 live births was 2.61. During the study period, an intraocular lens was implanted during 8.6% of the cataract extraction procedures performed in patients younger than 1 year and during 25.4% of those performed in older children (1 to 4 years old). Primary intraocular lens implantations were performed in 43 infants younger than 1 year (6-year mean: 5.9%) and in 77 children 1 to 4 years old (6-year mean: 11.6%).Conclusion:The percentage of pediatric hospital admissions with discharge diagnoses of congenital or infantile cataract remained fairly stable from 1999 through 2004; rates were higher in children 1 to 4 years old than in children younger than 1 year. The percentage of hospitalizations for cataract that involved surgical extraction was higher in children 1 to 4 years old. It decreased over time in both age groups. Ophthalmologists in Italy use intraocular lens implantation in children who are at least 1 year old, although this procedure is not common.

Purpose: To evaluate the efficacy and safety of intravitreal bevacizumab in proliferative diabetic retinopathy (PDR) patients. Methods: This interventional case series study included 15 eyes of 10 patients with bilateral PDR: 13 eyes with severe PDR and active new vessels (NV) and two eyes with recurrent vitreous haemorrhages. Study eyes received a single intravitreal injection of 1.25 mg (0.05 ml) bevacizumab. All eyes were followed up for 3 months, and eight of them for 9 months. Reinjection was performed in three eyes 4–6 months after the first injection. Study eyes were evaluated by fluorescein angiography at baseline, 1, 3 and 9 months. Quantitative planimetric analysis (QPA) of NV area was measured before and after treatment. All eyes received or completed panretinal photocoagulation (PRP) 1 month after the first injection. Results: As early as at 1 month, all study eyes had a regression (paired t-test, P = 0.01) of QPA-estimated NV area. The eyes with recurrent vitreous haemorrhages had clearing of bleeding. These early effects were maintained at 3 months for all eyes and tended to be stable at 9 months. The fast and measurable efficacy of bevacizumab allowed a subsequent complete and safe PRP. Conclusion: Intravitreal bevacizumab did not reveal any side-effects and was effective in the regression of NV areas and the resolution of vitreous haemorrhages. This approach is potentially useful in allowing (within a planned temporal window) a safe and efficient PRP to be performed while minimizing the risk of its complications.

To evaluate the retinal function and the neural conduction along the visual pathways after treatment with citicoline eye drops in patients with open angle glaucoma (OAG).Fifty-six OAG patients (mean age 52.4 ± 4.72 years, IOP18 mmHg with beta-blocker monotherapy only) were enrolled. Of these, 47 eyes completed the study: 24 OAG eyes were treated with topical citicoline (OMK1®, Omikron Italia, 3 drops/day) (GC eyes) over a 4-month period (month 4) followed by a 2-month period of citicoline wash-out (month 6), and another 23 OAG eyes were only treated with beta-blocker monotherapy (GP eyes). In GC and GP eyes, pattern electroretinogram (PERG) and visual evoked potentials (VEP) were assessed at baseline and at months 4 and 6 in both groups.At baseline, similar (ANOVA, p 0.01) PERG and VEP values in GC and GP eyes were observed. After treatment with topical citicoline, a significant (p 0.01) increase of PERG P50-N95 and VEP N75-P100 amplitudes, and a significant (p 0.01) shortening of VEP P100 implicit times were found. In GC eyes, the shortening of VEP P100 implicit times was correlated significantly (p 0.01) with the increase of PERG P50-N95 amplitudes. After a 2-month period of topical Citicoline wash-out, PERG and VEP values were similar (p 0.01) to baseline ones. GP eyes showed not significant changes of PERG and VEP values during the entire follow-up.Topical treatment with citicoline in OAG eyes induces an enhancement of the retinal bioelectrical responses (increase of PERG amplitude) with a consequent improvement of the bioelectrical activity of the visual cortex (shortening and increase of VEP implicit time and amplitude, respectively).

To differentiate the bioelectrical cortical responses driven by axons from central and mid-peripheral retina in Leber’s hereditary optic neuropathy (LHON) by using multifocal visual evoked potentials (mfVEP). Seventeen genetically confirmed LHON patients (33.35 ± 8.4 years, 17 eyes) and 22 age-matched controls (C) (38.2 ± 6.0 years, 22 eyes) were studied by mfVEP and optical coherence tomography. MfVEP P1 implicit time (P1 IT, ms) and response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg2) of the second order binary kernel were measured for five concentric retinal areas between the fovea and mid-periphery: 0–20 degrees (R1 to R5). Mean mfVEP P1 ITs and N1-P1 RADs at all five foveal eccentricities were significantly different (p

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies.Methods and findingsData sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls.Results11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p

Purpose: To assess short-term changes in macular function after transpupillary thermotherapy (TTT) in patients with occult subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD), using focal electroretinography (FERG). Methods: Twenty-five patients with occult subfoveal CNV due to AMD were treated with TTT delivered using an infrared (810 nm) diode laser (spot size 3.0 mm, laser power 400–600 mW, duration 60 seconds). All patients were clinically evaluated before, 1 and 6 weeks after treatment. Snellen visual acuity (VA) was measured at each visit. Fluorescein angiography (FA) was performed at baseline and 6 weeks after TTT. Focal ERGs were recorded in all patients immediately before and 1 week after TTT in response to an 18-degree diameter, 41 Hz flickering spot (630 nm) centred on the fovea, presented on a steady background in Maxwellian view. A subgroup of 12 patients was also re-tested by FERG at 6-weeks post-TTT. Results: No significant changes in mean FERG amplitude and phase were observed across the different recording sessions before and after TTT. One week after TTT, four patients had significant (>2 SD from baseline variability) increases in FERG amplitude and/or phase advances, one had a decrease in amplitude and four had phase delays, compared to baseline. The remaining 15 patients had stable FERGs. Six weeks after TTT, four patients had significant increases in FERG amplitude and/or phase advances, four had decreases in amplitude and/or phase delays, and four had stable FERGs, compared to baseline. Improvement in FERG parameters after TTT was always associated with an improvement in VA and a decrease in exudation. Patients with post-TTT FERG deterioration had stable or deteriorated clinical pictures. At either 1 or 6 weeks post-TTT, the FERG amplitude increase was inversely correlated (p

Purpose: To evaluate regional cone system function after uncomplicated retinal detachment (RD) surgery, by recording focal electroretinograms (FERGs) from the central and paracentral regions of the posterior pole. Methods: FERGs in response to either a central (eccentricity: 0–2.25 deg) or a paracentral annular (2.25–9 deg) uniform field, presented on a light adapting background and sinusoidally flickered at 41 Hz (95% modulation depth, 93 cd/m2 mean luminance) were recorded from 16 eyes (16 patients) 2 weeks to 420 months following uncomplicated RD surgery (encircling procedure with or without scleral buckling). Pre-operatively, 10 out of 16 eyes had a macular RD. Mean time elapsed from onset of symptoms to surgery was 20 days (range: 5–90 days). Post-operatively, visual acuity ranged 0.1 to 1.0. Eight age-matched normal subjects served as controls. Amplitude and phase of the FERG fundamental harmonic were measured. Results: Compared to control eyes, affected eyes’ central and paracentral FERGs were on average reduced in amplitude (by 40% and 28%, respectively, p

To evaluate retinal restoration after subfoveal perfluorcarbon liquid (PFCL) bubble removal by means of autofluorescence, infrared, and spectral domain optical coherence tomography over 2 years of follow-up.A 62-year-old patient underwent two 23-gauge vitrectomies in attempt to remove subretinal PFCL retained under the fovea secondary to retinal detachment surgery in the left eye. We assessed best-corrected visual acuity, fundus biomicroscopy, retinal imaging by autofluorescence, infrared, and spectral domain optical coherence tomography at the first observation of retained PFCL, 1 day after the first attempt of PFCL removal, and 1, 30, 90, and 180 days, and 2 years after the second successful removal surgery.The best-corrected visual acuity improved from 5 to 45 Early Treatment of Diabetic Retinopathy Study letters (1.0 to 0.2 logMAR units) at the end of follow-up. Spectral domain optical coherence tomography scans showed progressive reorganization of the outer limiting membrane and significant restoration of the inner/outer segment photoreceptors junction 2 years after surgery.Subfoveal PFCL is believed to cause photoreceptor damage in some eyes, probably because of mechanical compression. Innovative methods of imaging such as spectral domain optical coherence tomography and confocal scanning laser ophthalmoscope with infrared and autofluorescence, allow early and clear detection of subfoveal retained PFCL, as well as careful follow-up and easy differential diagnosis. Surgical removal leads to prompt retinal morphologic restoration and functional improvement enduring over time.

To explore functional retinal changes in neovascular AMD patients (nAMD) treated with ranibizumab 0.5 mg combined with photodynamic therapy (PDT) 3 days after the first injection in the long term.Patients with no prior treatment for nAMD were treated with 3 injections of ranibizumab 0.5 mg 1 month apart and a single session of standard PDT 3 days after the first injection. Best-corrected visual acuity and time-domain OCT at baseline and every 28 ± 2 days were performed; microperimetry at 3, 6, and 12 months and multifocal electroretinogramm (mfERG) at 3 and 12 months were repeated. Fluorescein angiography and vision-related quality-of-life questionnaire were performed at baseline and 12 months.12/15 nAMD patients completed the 12 months study and received an average of 3.4 ± 0.7 injections. Mean VA changed from 54.67 ± 15.72 to 59.0 ± 24.77 letters (p = 0.371), while mean retinal sensitivity from 5.5 ± 4.8 to 6.6 ± 6.0 dB (p = 0.216). MfERG N1-P1 response amplitude densities (RADs) were significantly different from baseline (p0.01) in the central 0°-2.5°, whereas in the peripheral retinal areas (2.5°-20°), not significant (p0.01) changes in N1-P1 RADs were detected. The "general vision" VFQ-25 subscale showed a statistically significant improvement at 3 and 12 months.Ranibizumab 0.5 mg combined with standard PDT 3 days after the first injection determines an improvement of mfERG values in the retinal central area in nAMD patients in long-term follow-up.